The long-term goal of this research is to develop new and effective treatments for drug addiction. We recently discovered that several agents blocking cholinergic alpha3beta4 nicotinic receptors reduce morphine, methamphetamine and nicotine self-administration in rats. In the brain alpha3beta4 nicotinic receptors are preferentially localized in the medial habenula and interpeduncular nucleus. Since the 1980's it has been known that the habenulo-interpeduncular pathway functions as a reward system that is separate from the mesolimbic pathway. Although it has long been known that the habenulo-interpeduncular pathway and the mesolimbic pathway interact and probably modulate each other, few studies have explored how this occurs and how manipulations of one can affect the other. The goal of this proposal is to examine the role of cholinergic mechanisms in the habenulo-interpeduncular pathway as a potential substrate for new treatments. The central hypothesis is that blocking cholinergic transmission in the habenulo-interpeduncular pathway will attenuate drug self-administration. Research will be organized into three specific aims: (1) We will establish that habenulo-interpeduncular cholinergic transmission influences drug self-administration. Our working hypothesis is that nicotinic antagonists, locally administered into the medial habenula or interpeduncular nucleus, will attenuate the intravenous self-administration of prototypicai drugs of abuse (morphine, methamphetamine, and nicotine). (2) We will establish that drugs of abuse enhance cholinergic transmission in the habenulo-interpeduncular pathway. Activation of the cholinergic habenulo-interpeduncular pathway may be an alternate or supplementary mechanism mediating or modulating the rewarding effects of drugs of abuse. Our working hypothesis is that drugs of abuse will raise extracellular levels of acetylcholine in the medial habenula and/or interpeduncular nucleus. (3) We will establish that the cholinergic habenulo-interpeduncular pathway modulates the dopaminergic mesolimbic pathway. Our working hypothesis is that nicotinic antagonists, locally administered into the medial habenula or interpeduncular nucleus, will attenuate the effects of abused drugs on extracellular levels of dopamine in the nucleus accumbens. The work proposed here may ultimately result in new kinds of treatments for drug abuse.